2.1 Salts of Aminoimidazole Carboxamide
AICA orotate, also referred to as "Orazamide Orotate" is incorporated into animal nucleic acids and possesses the ability to prevent necrosis of liver induced by acute and chronic hepatic damage in animals. Miller, C. S. et al., 1950, Science 112: 654.
2.1.1 Chemical Nature and Properties of Salts of Aminoimidazole Carboxamide
Orazamide is available in different forms as: 5-aminoimidazole-4-carboxamide orotate, 4-amino-5-imidazole carboxamide orotate or a combination of 1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidine carboxylic acid with 5-amino-1H-imidazole-4-carboxamide (1:1) or a combination of orotic acid with 5(or 4)-aminoimidazole-4(or 5)-carboxamide (1:1). The C5 amine group on the imidazole ring can be attached to the C4 carboxyl group of orotic acid or any other organic acid which is chemically compatible to the body: ##STR1##
2.1.2 Metabolic Effect of Orotic Acid
Any kind of organic or inorganic acid which is clinically compatible with the body may be selected to be reacted with AICA, an intermediate in the purine pathway. Especially desirable are orotic, lactic, succinic, maleic, citric, tartaric, gluconic, galactonic, hydrochloric, phosphoric and penta or poly hydroxycarboxylic acids.
Orotic acid is an intermediate in the pyrimidine pathway and its main source in human and animal diet is bovine milk and its products.
2.2 Alcohol and Liver Disease
An association of alcohol with damage to the liver rests primarily on the clinical observation that cirrhosis occurs in-patients consuming large amounts of ethanol. Ethanol has been shown to have a variety of toxic effects on livers in otherwise normal animals, including normal men and women.
Alcohol abuse costs the U.S. more than one hundred and sixteen billion dollars per year, of which about twelve percent is for direct costs of medical care. Advertising, counter advertising and depiction in the public media, 1986, JAMA 256: 1485. The basic reason for the large epidemic of alcohol-related disease is that ethanol is an effective drug in relieving anxiety, depression and the pressures of modern society. The easy availability of ethanol and the social acceptability of ethanol consumption are advertised widely and aggressively. The public seems unaware that chronic use of ethanol in the absence of addiction can lead to serious medical illness and/or the development of social consequences. About three quarters of the population of the United States uses ethanol. The incidence of alcoholism in the United States is approximately seven percent, being higher for men (11 percent) than for women (4.08 percent). Alcohol Health and Research World, 1995, 18: 243-8.
Prevention and/or treatment of alcoholism is a problem for which there are no certain answers. Therefore, an understanding of the biochemical basis for the hepatotoxicity of ethanol and its eventual control may provide an effective means to reduce and manage alcohol related liver diseases and medical complications.
2.3 Therapeutic Drugs and Liver Disease
Drug-induced liver disease is encountered rarely in general practice but accounts for between two to three percent of all admissions due to adverse drug reactions. Lewis, J. H., et al., 1989, Med. Clin. North Am. 73: 775. Published compilations of drug-related liver pathology list between 500 and 1000 therapeutic agents that have been implicated in the etiology of various liver diseases. Zimmerman, H. J., 1990, Semin. Liver. Dis. 10: 322.
Drugs with the potential for producing liver injury are divided into the "direct" or "predictable" hepatotoxins and "unpredictable" hepatotoxins. Direct hepatotoxins produce liver damage in a predictable, dose-dependent fashion, and they produce liver cell necrosis that affects predominantly a particular region of the liver lobule. Unpredictable hepatotoxins produce liver injury that is diffuse, consisting of necrosis and/or cholestasis, usually associated with a significant inflammatory reaction. Despite significant advances in the understanding of hepatotoxicity, the mechanisms by which certain drugs injure or kill the liver cell, or alter its function remain largely unknown and uncontrolled.
2.4 Industrial and Environmental Toxins and Liver Disease
The liver's potential for injury by environmental or occupational/industrial toxins is very high because it is the first organ after the gastrointestinal tract that is exposed to these agents, also known as xenobiotics. Hepatic metabolism usually detoxifies these agents. However, hepatic metabolism of xenobiotics can result in metabolites that are considerably more hepatotoxic than the parent chemicals. The hepatotoxic effects that result in humans from accidental or intentional exposures to xenobiotics or toxins range from mild liver dysfunction to necrosis. Xenobiotics may react with nutrients, destroy them or make them unavailable because of altered absorption or changes in detoxification or metabolic rates. Nutritional deficiencies in turn may enhance the toxic effects of xenobiotics. The realization that commonly used chemical compounds present health hazards has stirred considerable apprehension not only for industrial workers exposed directly to these agents but also for the general public who unwittingly get exposed to these ubiquitous noxious agents in the environment, in the food they eat or in their homes.